Synthesis process, and crystalline form of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]proxy}benzamide hydrochloride and pharmaceutical compositions containing it

ABSTRACT

Industrial synthesis process for, and crystalline form I of, the compound of formula (I): 
                         
and also crystalline form I of the associated free base.
 
     Medicinal products containing the same which are useful in the treatment of disorders of the histaminergic system.

The present invention relates to a process for the industrial synthesisof 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride of formula (I):

The present invention relates also to crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride, to a process for its preparation and also topharmaceutical compositions containing it.

Crystalline form I of the free base of the compound of formula (I) is,moreover, also obtained by the process of the invention and forms anintegral part of the invention, as do pharmaceutical compositionscontaining it.

4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hasthe characteristic of interacting with central histaminergic systems invivo. These properties provide it with activity in the central nervoussystem and, more especially, in the treatment of cognitive deficienciesassociated with cerebral aging and with neurodegenerative diseases.

4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, itspreparation in the form of an oxalate and its therapeutic use have beendescribed in Patent Application WO2005/089747.

In view of the pharmaceutical value of this compound it was important tobe able to obtain it by an effective synthesis process that is readilytransferable to the industrial scale, yielding4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride in a good yield and with excellent purity.

It was also important to be able to obtain4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride in a well-defined, perfectly reproducible crystalline formhaving valuable filtration characteristics and ease of formulation.

The Patent Application WO2005/089747 describes obtaining4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamideoxalate in three steps starting from 4-hydroxybenzonitrile, whichundergoes an O-alkylation reaction before being coupled to anoctahydrocyclopenta[c]pyrrole-type ring system to form4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzonitrile.The latter compound is finally subjected to basic hydrolysis in order toyield 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,which is crystallised in the form of an oxalate. The yield for thesethree steps is 46.6%.

The present invention relates to a new industrial synthesis processwhich yields4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride with satisfactory purity from the pharmaceutical point ofview and in an effective yield from the industrial point of view. Byvirtue of this process it is possible to ensure a very low level ofgenotoxic impurities, which is compatible with regulatory requirements.

The present invention relates, more specifically, to a process for theindustrial synthesis of the compound of formula (I):

which process is characterised in that the compound of formula (II):

is reacted with ammonia at a temperature greater than 100° C. to formthe compound of formula (III):

which is reduced to yield the bicyclic amine of formula (IV):

which latter compound is subsequently subjected:

either to a coupling reaction, under basic conditions in a polar medium,with a compound of formula (V):

wherein Y represents —CH₂-Hal wherein Hal is a halogen, or a group—CH₂—OSO₂—R wherein R is a (C₁-C₆)alkyl group or a —C₆H₄—CH₃ group,

or to reductive amination, in an acid medium, with a compound of formula(V′):

wherein R′ and R″ represent, each independently of the other, a(C₁-C₆)alkyl group, or R′ and R″ together form a group —(CH₂)_(n)—wherein n=2-3, or one of the groups R′ and R″ represents a hydrogen atomand the other represents a (C₁-C₆)alkyl group,

or to reductive amination with the compound of formula (V″):

to yield the free base of the compound of formula (I), which is placedin the presence of HCl to form the compound of formula (I), which isisolated in the form of a solid.

In a preferred embodiment of the invention, the reaction mixtureobtained at the end of the reaction of the compound of formula (II) withammonia is subjected to pyrolysis. The pyrolysis in question is carriedout preferably at a temperature greater than or equal to 200° C., andeven more preferably at a temperature greater than or equal to 280° C.

Conversion of the compound of formula (III) into the compound of formula(IV) is advantageously carried out in the presence of hydrogen and ametal or metal-containing catalyst.

Preference is given to the compound of formula (V) being4-(3-chloropropoxy)benzamide.

The coupling reaction of the compound of formula (IV) with the compoundof formula (V) is preferably carried out in the presence of a carbonate,an amine or a hydroxide. Among the preferred carbonates, amines andhydroxides there may be mentioned potassium carbonate, caesiumcarbonate, triethylamine, pyridine, potassium hydroxide, sodiumhydroxide and lithium hydroxide. Even more preferably, the couplingreaction of the compound of formula (IV) with the compound of formula(V) is carried out in the presence of potassium carbonate ortriethylamine. This reaction is moreover advantageously performed in apolar medium composed of one or more polar solvents selected from water,alcohols, ketones, ethers, amides, DMSO and acetonitrile. Preferredalcohols are methanol, ethanol, isopropanol and butanol. The preferredsolvents also include acetone and methyl ethyl ketone among the ketones,tetrahydrofuran, methyltetrahydrofuran and cyclopentyl methyl etheramong the ethers, and also N-methyl-2-pyrrolidone among the amides. Evenmore preferably, the coupling reaction of the compound of formula (IV)with the compound of formula (V) is performed in a water/acetonitrilemixture or a water/isopropanol mixture.

In the case of reductive amination, in an acid medium, of the compoundof formula (IV) with a compound of formula (V′), the latter ispreferably 4-(3,3-diethoxypropoxy)benzamide.

Furthermore, the step of forming a salt from the free base of thecompound of formula (I) in the presence of HCl preferably takes place ina solvent selected from water, acetone and an alcohol. Preferredalcohols are methanol, ethanol and isopropanol. Acetone and isopropanolare more especially preferred for this salt formation step.

Optionally, the compound of formula (I) isolated at the end of the saltformation step is subjected to recrystallisation.

It is important to emphasise that this synthesis process makes itpossible to obtain the compound4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,exclusively, in a satisfactory yield on the industrial scale, and notits trans homologue. Besides this advantage, it makes it possible tokeep the levels of genotoxic impurities (especially4-(3-chloropropoxy)benzamide) present in the batches well below theregulatory threshold.

The compounds of formula (V) wherein Y represents a group —CH₂—OSO₂—Rwherein R is a (C₁-C₆)alkyl group or a —C₆H₄—CH₃ group and the compoundsof formula (V′) are new and useful as intermediates in the synthesis ofcompound of formula (I). The compound of formula (V″) is also useful asintermediate in the synthesis of compound of formula (I).

The invention relates also to crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride obtained according to the process described above. Thiscrystalline form is well-defined, perfectly reproducible andconsequently has valuable characteristics of filtration, drying,stability and ease of formulation.

Crystalline form I of the compound of formula (I) is characterised by anX-ray powder diffraction diagram having the following diffraction lines(Bragg's angle 2 theta, expressed in degrees ±0.2°): 16.97°, 17.84°,18.90°, 20.32°, 23.87°, 27.10°, 27.86° and 30.34°.

More specifically, crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride is characterised further by the X-ray powder diffractiondiagram below, measured using a PANalytical X'Pert Pro MPDdiffractometer with an X'Celerator detector, and expressed in terms ofline position (Bragg's angle 2 theta, expressed in degrees ±0.2°) andinterplanar distance d (expressed in Å):

Angle 2-theta Interplanar Line no. (degrees) distance (Å) 1 16.97 5.2192 17.84 4.967 3 18.90 4.690 4 20.32 4.366 5 23.87 3.724 6 27.10 3.288 727.86 3.200 8 30.34 2.943

Besides that, form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamidehydrochloride has been characterised by Raman spectroscopy. Significantpeaks were observed in the following locations: 1676 cm⁻¹, 1606 cm⁻¹,1564 cm⁻¹, 1152 cm⁻¹, 830 cm⁻¹ and 296 cm⁻¹.

Alternatively, form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamidehydrochloride may be characterised by the X-ray powder diffractiondiagram having the 8 significant lines given above and also by a Ramanspectrum having a significant peak at the location 1606 cm⁻¹ or 1676cm⁻¹.

Obtaining this crystalline form has the advantage of allowing especiallyrapid and efficient filtration and also the preparation ofpharmaceutical formulations having a consistent and reproduciblecomposition, which is especially advantageous when those formulationsare intended for oral administration. Furthermore, form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride has noteworthy properties of immediate dissolution.

The form thereby obtained is sufficiently stable to allow its storagefor an extended period without particular conditions for temperature,light, humidity or oxygen levels. More specifically, form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamidehydrochloride has been found to be very stable over periods of up to 18months under the following conditions:

-   -   at 25° C. with a humidity level of 60% in a double bag of        polyethylene,    -   at 30° C. with a humidity level of 65% in a double bag of        polyethylene,    -   at 30° C. with a humidity level of 85% in a double bag of        polyethylene.

Another aspect of the invention relates to crystalline form I of thefree base of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide obtained according to the process describedabove. This crystalline form is well-defined and perfectly reproducible.Obtaining this form and isolating it in the course of the synthesisprocess for the hydrochloride of formula (I) described above make itpossible to eliminate a large proportion of the genotoxic impuritiespresent in the batches.

Crystalline form I of the free base of the compound of formula (I) ischaracterised by its X-ray powder diffraction diagram having thefollowing diffraction lines (Bragg's angle 2 theta, expressed in degrees±0.2°): 6.25°, 12.55°, 17.74°, 18.19°, 19.43°, 20.72°, 21.00°, 23.50°and 27.00°.

More specifically, crystalline form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide ischaracterised further by the X-ray powder diffraction diagram below,measured using a PANalytical X'Pert Pro MPD diffractometer with anX'Celerator detector, and expressed in terms of line position (Bragg'sangle 2 theta, expressed in degrees ±0.2°) and interplanar distance d(expressed in Å):

Angle 2-theta Interplanar Line no. (degrees) distance (Å) 1 6.25 14.1312 12.55 7.049 3 17.74 4.997 4 18.19 4.873 5 19.43 4.565 6 20.72 4.284 721.00 4.226 8 23.50 3.782 9 27.00 3.297

In addition, form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hasbeen characterised by Raman spectroscopy. Significant peaks wereobserved in the following locations: 292 cm⁻¹, 618 cm⁻¹, 1045 cm⁻¹, 1483cm⁻¹, 1568 cm⁻¹, 1683 cm⁻¹.

Alternatively, form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide may becharacterised by the X-ray powder diffraction diagram having the 9significant lines given above and also by a Raman spectrum having asignificant peak at the location 1683 cm⁻¹.

Finally, form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hasalso been characterised by solid-state NMR spectroscopy. Significantpeaks were observed at 112.2 ppm, 119.2 ppm, 127.2 ppm, 128.6 ppm, 132.4ppm, 162.2 ppm and 173.2 ppm. More precisely, the ¹³C CP/MAS (CrossPolarization Magic Angle Spinning) spectra have the following peaks(expressed in ppm±0.2 ppm):

Chemical shift Peak no. (ppm) 1 173.2 2 162.2 3 132.4 4 128.6 5 127.2 6119.2 7 112.2 8 67.1 9 64.0 10 59.7 11 52.1 12 44.5 13 42.8 14 31.5 1530.8 16 30.2 17 26.2

Pharmacological study of form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride and also that of form I of its free base have shownsubstantial activity on the central nervous system which makes itpossible to establish its usefulness in the treatment of cognitive andpsycho-behavioural disorders associated with cerebral aging and withneurodegenerative diseases, and also in the treatment of mood disorders,attention-deficit hyperactivity syndrome, obesity and pain.Neurodegenerative diseases more especially targeted are Alzheimer'sdisease, Parkinson's disease, Pick's disease, Korsakoff's disease, Lewybody dementias, frontal and subcortical dementias, frontotemporaldementias and vascular dementias.

The invention relates also to pharmaceutical compositions comprising asactive ingredient crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamidehydrochloride, or crystalline form I of its free base, together with oneor more appropriate, non-toxic, inert excipients. Among thepharmaceutical compositions according to the invention there may be moreespecially mentioned those that are suitable for oral, parenteral(intravenous or subcutaneous) or nasal administration, tablets ordragées, granules, sublingual tablets, capsules, lozenges,suppositories, creams, ointments, dermal gels, injectable preparations,drinkable suspensions and chewing gums.

The useful dosage can be varied according to the nature and severity ofthe disorder, the administration route and also the age and weight ofthe patient. The useful dosage varies from 1 mg to 100 mg per day, inone or more administrations. Preferably, crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride is administered at daily doses (expressed as free baseequivalent) of 2 mg, 5 mg and 20 mg (or, that is to say, 2.25 mg, 5.63mg and 22.52 mg of the hydrochloride).

The Examples hereinbelow illustrate the invention.

PREPARATION 1 4-(3-Chloropropoxy)benzamide

10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium carbonate and 83 kgof acetonitrile are introduced into a reactor. The mixture is stirredand then there are added 24.14 kg of a solution of1-bromo-3-chloropropane. The reaction mixture is heated at reflux for 4hours. Water (105 L) is added in the hot state, the mixture is thencooled to 5° C. and filtered. The filter cake is washed with water andthen with acetonitrile. The title product is obtained in the form of apowder in a yield of 82%.

Melting point: 144° C.

PREPARATION 2 4-(3-Oxopropoxy)benzamide Step A:4-(3,3-Diethoxypropoxy)benzamide

500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL ofDMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask. Thereaction mixture is stirred at 100° C. for 18 hours and then 5 mL ofwater are added. The aqueous phase is extracted with ethyl acetate, andthen the organic phases are collected, washed with water andconcentrated under reduced pressure. The product is obtained in the formof a powder in a yield of 89% and with a chemical purity of 95%.

Melting point: 108° C.

Step B: 4-(3-Oxopropoxy)benzamide

5 g of the product obtained in Step A, 100 ml of THF and 94 mL of 1Nhydrochloric acid solution are added to a flask. The mixture is stirredat ambient temperature for 1 hour. The aqueous phase is extracted withdichloromethane, and then the organic phases are concentrated underreduced pressure. The product is obtained in the form of a solid in ayield of 96% and with a chemical purity of 93%.

EXAMPLE 14-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

Load 1 kg of diethyl 1,2-cyclopentanedicarboxylate and 1.02 kg of 27%ammonia into an autoclave. The reaction mixture is heated in theautoclave at a temperature of 130° C. for a minimum of 4 hours. Aftercooling to 60° C. and depressurisation, evaporation of the solvent iscarried out. The residue is then subjected to pyrolysis at 280° C. for 1hour. The imide is purified by distillation in vacuo (4-12 mbars) at atemperature of 200° C. After isolation, the title product is obtained ina yield of 96%.

Melting point: 89° C.

Step B: cis-Octahydrocyclopenta[c]pyrrole

1 kg of the imide of Step A, 250 g of copper chromite and 2 L of dioxaneare loaded into a reactor. The reaction mixture is stirred at atemperature of 265° C. and under a hydrogen pressure of 205 bars untilthe absorption of hydrogen is complete. After cooling of the reactor,the catalyst is filtered off.

The hydrogenation liquors are loaded into a separator and then 0.37 L ofwater is added. The pH is adjusted to a pH of less than 3 by addingsulphuric acid 96%. The lower, aqueous phase is drawn off. After adding2.5 L of water, the residual dioxane is removed by azeotropicdistillation with monitoring of the refractive index. The pH is thenbrought to 13 by adding 30% sodium hydroxide solution. The title productis purified by azeotropic distillation with water to obtain a 30%solution by weight in a yield of 83%.

Step C:4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide

13.35 kg of 4-(3-chloropropoxy)benzamide obtained according toPreparation 1, 10.33 kg of potassium carbonate and 168 kg ofacetonitrile are introduced into a reactor. The mixture is stirred.There are then loaded 34.74 kg of cis-octahydrocyclopenta[c]pyrrole in a30% aqueous solution, 26.7 L of water. The reaction mixture is heated atreflux until all the starting material has been consumed. Then water(13.3 L) is added. The mixture is cooled to 5° C., before being filteredand washed with water. The title product is obtained in the form of asolid in a yield of 81% and with a chemical purity of 96%.

¹H NMR: δ(600.13 MHz; DMSO-d6; 300K): 7.82 (d, 2H, J=9.0 Hz); 7.79 (bs,1H); 7.14 (bs, 1H); 6.95 (d, 2H, J=9.0 Hz); 4.06 (t, 2H, J=6.5 Hz); 2.57(m, 2H); 2.48 (m, 2H); 2.44 (bt, 2H, J=6.5 Hz); 2.14 (bd, 2H, J=7.5 Hz);1.86 (qt, 2H, J=6.5 Hz); 1.65-1.55 (m, 3H); 1.45-1.38 (m, 1H); 1.37-1.30(m, 2H)

where bs: broad singlet; bd: broad doublet; bt: broad triplet

Characterisation of the product thereby formed, using the techniquesgiven in Examples 6 to 8, demonstrated that the crystalline form I ofthe free base was obtained.

Step D:4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

14.69 kg of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and122 L of water are introduced into a reactor. A solution of 6.81 kg of37% hydrochloric acid in 11.54 L of water is also prepared. 13.75 kg ofthis acid solution are added to the reactor. The mixture is stirred for1 hour at ambient temperature, and then for 1 hour 30 minutes at 60° C.The suspension is filtered in the hot state and the filter is thenrinsed with water. A solvent change is then carried out on the filtrate,keeping the volume constant, in order to obtain an isopropanol/waterratio of 9/1. The product is isolated at 0° C. and the precipitateobtained is washed with isopropanol. The title product is finallyobtained in a yield of 89% and with a chemical purity greater than 99%.

Characterisation of the product thereby formed, using the techniquesgiven in Examples 4 to 5, demonstrated that the crystalline form I ofthe hydrochloride was obtained.

Step E:4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

The hydrochloride salt obtained in Step D is recrystallised from amixture of isopropanol (264 kg) and water (37.4 L). The mixture isheated at reflux for 45 minutes. The solution is filtered in the hotstate and then rinsed with isopropanol. Crystallisation is theninitiated at 55° C. The mixture is maintained at that temperature for 40minutes before being cooled to 0° C. After several hours, the product isisolated by filtration. After washing with isopropanol, the titleproduct is obtained in the form of a powder in a yield of 93% and with achemical purity greater than 99%.

Melting point: 213-215° C.

Characterisation of the product thereby formed, using the techniquesgiven in Examples 4 to 5, demonstrated that the crystalline form I ofthe hydrochloride was obtained.

EXAMPLE 24-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

The procedure is the same as that described in Step A of Example 1.

Step B: cis-Octahydrocyclopenta[c]pyrrole

The procedure is the same as that described in Step B of Example 1.

Step C:4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide

15.2 kg of 4-(3-chloropropoxy)benzamide, 40.28 kg ofcis-octahydrocyclopenta[c]pyrrole in 30% aqueous solution, 63.84 kg ofwater, 21.48 kg of isopropanol and 14.39 kg of triethylamine areintroduced into a reactor. The reaction mixture is stirred and heated atreflux until all the starting material has been consumed. The reactionmixture is then cooled to 20° C., before being filtered and washed witha mixture of isopropanol and water. The product is obtained in the formof a powder in a yield of 83% and with a chemical purity of 97%.

¹H NMR: δ(600.13 MHz; DMSO-d6; 300K): 7.82 (d, 2H, J=9.0 Hz); 7.79 (bs,1H); 7.14 (bs, 1H); 6.95 (d, 2H, J=9.0 Hz); 4.06 (t, 2H, J=6.5 Hz); 2.57(m, 2H); 2.48 (m, 2H); 2.44 (bt, 2H, J=6.5 Hz); 2.14 (bd, 2H, J=7.5 Hz);1.86 (qt, 2H, J=6.5 Hz); 1.65-1.55 (m, 3H); 1.45-1.38 (m, 1H); 1.37-1.30(m, 2H)

where bs: broad singlet; bd: broad doublet; bt: broad triplet

Characterisation of the product thereby formed, using the techniquesgiven in Examples 6 to 8, demonstrated that the crystalline form I ofthe free base was obtained.

Step D:4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

16.49 kg of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, 16.36kg of acetone, 6.76 kg of concentrated aqueous hydrochloric acid and18.96 kg of water are introduced into a reactor. The mixture is stirredand heated at 50° C. for 1 hour. The mixture is then filtered in the hotstate into a second reactor containing 57.67 kg of acetone and 1.65 kgof water. The mixture is then brought to reflux and 73.32 kg of acetoneare added. Reflux is maintained for 10 minutes and then cooling to 0° C.is carried out. The product is filtered off and the solid obtained iswashed with acetone. The product is obtained in the form of a powder ina yield of 85% and with a chemical purity greater than 99%.

Characterisation of the product thereby formed, using the techniquesgiven in Examples 4 to 5, demonstrated that the crystalline form I ofthe hydrochloride was obtained.

EXAMPLE 34-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride Step A: Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

The procedure is the same as that described in Step A of Example 1.

Step B: cis-Octahydrocyclopenta[c]pyrrole

The procedure is the same as that described in Step B of Example 1.

Step C: cis-Octahydrocyclopenta[c]pyrrole hydrochloride

2 g of cis-octahydrocyclopenta[c]pyrrole are dissolved in 10 mL ofethanol in a flask. The solution is cooled to 0° C., and there are thenadded 1.64 mL of concentrated hydrochloric acid solution (11M). Thereaction mixture is stirred at 20° C. for 30 minutes before beingconcentrated under reduced pressure. The reaction mixture is stirred inmethyl tert-butyl ether at 0° C. The product is isolated by filtrationin the form of a solid in a yield of 83% and with a chemical purity of99%.

Melting point: 126° C.

Step D:4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

915 mg of the product obtained in Step C, 1.65 g of sodiumtriacetoxyborohydride, 45 mL of THF and 7.5 mL of trimethyl orthoformateare added into a reactor. There are then added 1 g of the compoundobtained in Preparation 2. The reaction mixture is heated at 40° C. for50 minutes and then cooled to ambient temperature. There are then addeda saturated NaHCO₃ solution. The aqueous phase is extracted with ethylacetate, and then the organic phases are combined and washed with water.The organic phase is dried over MgSO₄, filtered and concentrated underreduced pressure. The residue is suspended in an isopropanol/watermixture in the presence of hydrochloric acid. The reaction mixture isheated at 40° C. then cooled to 5° C. The product is isolated byfiltration in the form of a solid in a yield of 33% and with a chemicalpurity of 98%.

Characterisation of the product thereby formed, using the techniquesgiven in Examples 4 to 5, demonstrated that the crystalline form I ofthe hydrochloride was obtained.

EXAMPLE 4 Crystalline Form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

Prior to recording the X-ray diffraction diagram, the samples obtainedaccording to the procedure described in one of Examples 1 to 3 weremilled for 30 seconds at 30 Hz in the presence of 100 μL of anhydrousethanol per 200 mg of active ingredient in a 25-ml stainless-steel jarcontaining 2 stainless-steel balls.

Recording of the data was carried out using a PANalytical X'Pert Pro MPDdiffractometer with an X'Celerator detector under the followingconditions:

-   -   Voltage 45 kV, current 40 mA,    -   Mounting: theta/theta,    -   Anode: copper,    -   K alpha-1 wavelength: 1.54060 Å,    -   K alpha-2 wavelength: 1.54443 Å,    -   K alpha-2/K alpha-1 ratio: 0.5    -   Measurement mode: continuous from 3° to 55° (Bragg's angle 2        theta) in increments of 0.017°,    -   Measurement time per step: 35.53 s.

The X-ray powder diffraction diagram of form I of the4-{3-[cis-hexahydrocyclopenta-[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride thereby obtained is expressed in terms of line position(Bragg's angle 2 theta, expressed in degrees ±0.2°), interplanardistance (expressed in Å) and relative intensity (expressed as apercentage relative to the most intense line). The significant lines arecollated in the following table:

Relative Angle 2-theta Interplanar intensity Line no. (degrees) distance(Å) (%) 1 16.97 5.219 9.7 2 17.84 4.967 21.6 3 18.90 4.690 100 4 20.324.366 41.8 5 23.87 3.724 15.4 6 27.10 3.288 44.7 7 27.86 3.200 6.6 830.34 2.943 21.7

The following parameters were thereby determined:

-   -   monoclinic crystalline unit cell,    -   unit cell parameters: a=10.6621 Å, b=10.4945 Å, c=15.6542 Å,        β=101.949°    -   space group: P 1 2₁/c 1 (14)    -   number of molecules in the unit cell: 4    -   volume of the unit cell: V_(unit cell)=1713.637 Å³    -   density: d=1.2590 g/cm³.

EXAMPLE 5 Crystalline Form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride

Form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride was characterised by Raman spectroscopy. The spectra wererecorded in reflection mode (PerkinElmer) and transmission mode (Cobalt)with laser focalisation of 785 nm and 830 nm respectively, using a CCDdetector. The wavelength shift depends on the material and ischaracteristic of that material, which allows analysis of the chemicalcomposition and of the molecular arrangement of the sample studied. Thespectra are acquired:

in reflection mode with a laser power of 400 mW, a spot size of 100 μm,five exposures of five seconds and a spectral resolution of 2 cm⁻¹,

in transmission mode with a laser power of 650 mW, a spot size of 4 mm,twenty exposures of 3 seconds and a spectral resolution of 2 cm⁻¹.

The spectral range explored ranges from 0 to 3278 cm⁻¹ in reflectionmode and from 37 to 2400 cm⁻¹ in transmission mode.

Significant peaks were observed at the following locations: 1676 cm⁻¹,1606 cm⁻¹, 1564 cm⁻¹, 1152 cm⁻¹, 830 cm⁻¹ and 296 cm⁻¹.

EXAMPLE 6 Crystalline Form I of the Free Base of4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide

Recording of the data was carried out using a PANalytical X'Pert Pro MPDdiffractometer with an X'Celerator detector under the followingconditions:

-   -   Voltage 45 kV, current 40 mA,    -   Mounting: theta/theta,    -   Anode: copper,    -   K alpha-1 wavelength: 1.54060 Å,    -   K alpha-2 wavelength: 1.54443 Å,    -   K alpha-2/K alpha-1 ratio: 0.5    -   Measurement mode: continuous from 3° to 55° (Bragg's angle 2        theta) in increments of 0.017°,    -   Measurement time per step: 35.53 s.

The X-ray powder diffraction diagram of form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamideobtained according to the process of one of Examples 1 to 3 is expressedin terms of line position (Bragg's angle 2 theta, expressed in degrees±0.2°), interplanar distance (expressed in Å) and relative intensity(expressed as a percentage relative to the most intense line). Thesignificant lines are collated in the following table:

Angle 2-theta Interplanar Relative Line no. (degrees) distance (Å)intensity (%) 1 6.25 14.131 6.6 2 12.55 7.049 16.3 3 17.74 4.997 100 418.19 4.873 7.3 5 19.43 4.565 13.3 6 20.72 4.284 32.2 7 21.00 4.226 7.78 23.50 3.782 51.4 9 27.00 3.297 5.9

EXAMPLE 7 Crystalline Form I of the Free Base of4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide

Form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide wascharacterised by Raman spectroscopy. The spectra were recorded intransmission mode (Cobalt) with laser focalisation of 830 nm using a CCDdetector. The wavelength shift depends on the material and ischaracteristic of that material, which allows analysis of the chemicalcomposition and of the molecular arrangement of the sample studied. Thespectra are acquired with a laser power of 650 mW, a spot size of 4 mm,twenty exposures of 0.9 second and a spectral resolution of 2 cm⁻¹. Thespectral range explored ranges from 37 to 2400 cm⁻¹.

Significant peaks were observed at the following locations: 292 cm⁻¹,618 cm⁻¹, 1045 cm⁻¹, 1483 cm⁻¹, 1568 cm⁻¹, 1683 cm⁻¹.

EXAMPLE 8 Crystalline Form I of the Free Base of4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide

Form I of the free base of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide wasalso characterised by solid-state NMR spectroscopy. The solid-state ¹³CNMR spectra were recorded at ambient temperature using a Bruker SBAvance spectrometer with a 4-mm CP/MAS SB VTN type probe under thefollowing conditions:

-   -   Frequency: 125.76 MHz,    -   Spectral width: 40 kHz,    -   Magic angle spinning rate: 13 kHz,    -   Pulse program: Cross Polarization with SPINAL64 decoupling        (decoupling power of 80 kHz),    -   Recycle delay: 10 s,    -   Acquisition time: 47 ms,    -   Contact time: 4 ms,    -   Number of scans: 4096.

The spectra thereby obtained were referenced relative to a sample ofadamantane.

The peaks observed are collated in the following table (expressed in ppm±0.2 ppm):

Chemical shift Peak no. (ppm) 1 173.2 2 162.2 3 132.4 4 128.6 5 127.2 6119.2 7 112.2 8 67.1 9 64.0 10 59.7 11 52.1 12 44.5 13 42.8 14 31.5 1530.8 16 30.2 17 26.2

EXAMPLE 9 Pharmaceutical Composition

Formula for the Preparation of 1000 Tablets Each Containing 5 mg ofActive Ingredient (Expressed as Equivalent to the Base):

Compound of Example 1 (expressed as equivalent to the base) . . . 5 g

Maize starch . . . 20 g

Maltodextrin . . . 7.5 g

Colloidal silica . . . 0.2 g

Sodium starch glycolate . . . 3 g

Magnesium stearate . . . 1 g

Lactose . . . 65 g

The invention claimed is:
 1. A crystalline form I of the compound offormula (I):

having an X-ray powder diffraction diagram exhibiting the followingdiffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°):16.97°, 17.84°, 18.90°, 20.32°, 23.87°, 27.10°, 27.86° and 30.34°. 2.The crystalline form I according to claim 1, having the following X-raypowder diffraction diagram, measured using a PANalytical X'Pert Pro MPDdiffractometer with an X'Celerator detector, and expressed in terms ofline position (Bragg's angle 2 theta, expressed in degrees ±0.2°) andinterplanar distance d (expressed in Å): Angle 2-theta Interplanar Lineno. (degrees) distance (Å) 1 16.97 5.219 2 17.84 4.967 3 18.90 4.690 420.32 4.366 5 23.87 3.724 6 27.10 3.288 7 27.86 3.200 8 30.34 2.943.


3. The crystalline form I according to claim 1, having a Raman spectrumexhibiting a significant peak at the location 1606 cm⁻¹ or 1676 cm⁻¹. 4.The crystalline form I according to claim 1, having a Raman spectrumexhibiting significant peaks at the locations 1676 cm⁻¹, 1606 cm⁻¹, 1564cm⁻¹, 1152 cm⁻¹, 830 cm⁻¹ and 296 cm⁻¹.
 5. A pharmaceutical compositioncomprising as active ingredient the crystalline form I of4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamidehydrochloride according to claim 1, in combination with one or morepharmaceutically acceptable, non-toxic, inert carriers.
 6. A crystallineform I of the free base of the compound of formula (I):

having an X-ray powder diffraction diagram exhibiting the followingdiffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°):6.25°, 12.55°, 17.74°, 18.19°, 19.43°, 20.72°, 21.00°, 23.50° and27.00°.
 7. The crystalline form I according to claim 6, having thefollowing X-ray powder diffraction diagram, measured using a PANalyticalX'Pert Pro MPD diffractometer with an X'Celerator detector, andexpressed in terms of line position (Bragg's angle 2 theta, expressed indegrees ±0.2°) and interplanar distance d (expressed in Å): Angle2-theta Interplanar Line no. (degrees) distance (Å) 1 6.25 14.131 212.55 7.049 3 17.74 4.997 4 18.19 4.873 5 19.43 4.565 6 20.72 4.284 721.00 4.226 8 23.50 3.782 9 27.00 3.297.


8. The crystalline form I according to claim 6, having a Raman spectrumexhibiting a significant peak at the location 1683 cm⁻¹.
 9. Thecrystalline form I according to claim 6, having a Raman spectrumexhibiting significant peaks at the locations 292 cm⁻¹, 618 cm⁻¹, 1045cm⁻¹, 1483 cm⁻¹, 1568 cm⁻¹, 1683 cm⁻¹.
 10. A crystalline form I of thefree base of the compound of formula (I):

having a solid-state ¹³C CP/MAS NMR spectrum exhibiting the followingpeaks (expressed in ppm ±0.2 ppm): 112.2 ppm, 119.2 ppm, 127.2 ppm,128.6 ppm, 132.4 ppm, 1612 ppm and 173.2 ppm.
 11. The crystalline form Iaccording to claim 10, having a solid-state ¹³C CP/MAS NMR spectrumexhibiting the following peaks (expressed in ppm ±0.2 ppm): Chemicalshift Peak no. (ppm) 1 173.2 2 162.2 3 132.4 4 128.6 5 127.2 6 119.2 7112.2 8 67.1 9 64.0 10 59.7 11 52.1 12 44.5 13 42.8 14 31.5 15 30.8 1630.2 17 26.2.


12. A pharmaceutical composition comprising as active ingredient thecrystalline form I of the free base of the compound of formula (I)according to claim 6, in combination with one or more pharmaceuticallyacceptable, non-toxic, inert carriers.